Dementia is estimated to affect 25 million people worldwide, of which 30-70% are Alzheimer's disease (AD) and 10% frontotemporal dementia (FTD). Neuropathological evidence points to a neuronal/synaptic polioencephalopathy with the disease beginning in the grey matter with accumulation of misfolded beta amyloid and/or tau protein, and progressing along extant fiber pathways via secondary Wallerian degeneration, disconnection, loss of signaling, axonal reaction and post-synaptic dendrite retraction. Atrophy patterns captured from longitudinal MRI via segmentation, atlas-based parcellation, and volumetric analysis indicate that progression follows vulnerable fiber pathways rather than proximity. This view is supported by recent studies showing alterations in brain networks due to neurodegeneration. Amyloid deposition, metabolism and atrophy in AD show spatially distinct involvement of the posterior temporal heteromodal network, while the frontal (behavioral) variant of FTD, bvFTD, appears restricted to the orbitofrontal network. These findings led to the network-degeneration view that various dementias selectively target distinct intrinsic brain networks.
This view is strongly supported by neuropathological evidence that numerous disease proteins, including alpha-synuclein, beta-amyloid, and TDP-43, have the capacity to misfold and march throughout local and then long-range circuits via transsynaptic spread. Misfolded proteins can trigger misfolding of adjacent same-species proteins, which in turn cascade along neuronal pathways. Pathological tau conformers can induce non-folded tau to adopt pathological conformations. Tau misfolding could propagate from the exterior to interior of a cell. These findings suggest a “prion-like” mechanism of transmission underlying all dementias.